This project assesses the safety and efficacy of pharmacological treatments of cocaine and opioid abuse/dependence in clinical trials. The partial opiate agonist buprenorphine is a safe and effective treatment for opiate dependence. Some preclinical studies and uncontrolled clinical case series have suggested that buprenorphine might also be effective in reducing cocaine use by opiate addicts. A double-blind, controlled clinical trial that directly evaluated the efficacy of buprenorphine in reducing both opiate and cocaine use in 200 dually opiate- and cocaine-dependent patients was completed in the past year. Preliminary analyses indicated that buprenorphine decreased both cocaine and opiate use (based on urinalysis) and that the highest dose decreased cocaine use to a greater degree than the lower doses. Medically supervised withdrawal from opioids is a commonly used treatment but is usually not effective in establishing long-term abstinence because patients frequently relapse soon after completion of the withdrawal. A procedure for initiating naltrexone maintenance during withdrawal treatment was developed to provide a more effective post-withdrawal treatment that includes pharmacological treatment with opioid antagonists. The efficacy of buprenorphine-naltrexone combinations has been tested in a one pilot and one randomized double-blind clinical trials. The results of the second study replicated the original pilot study showing that administration of naltrexone on day 2 may increase opiate withdrawal at the beginning of treatment but is generally safe and effective. A third phase of the study is ongoing to further refine the buprenorphine/naltrexone dosing parameters to identify optimal procedures for initiating naltrexone treatment. Preliminary analysis of the studies described above suggest that buprenorphine is safe and effective for treatment of opioid dependence in HIV-positive patients. A study is currently underway to compare buprenorphine, clonidine, and methadone in the management of opioid dependence in patients hospitalized for HIV-related illnesses. Evidence from preclinical studies suggests that the reinforcing effects of cocaine are related to its inhibition of dopamine reuptake. An open trial testing the safety and efficacy of combination treatment with bupropion and bromocriptine, agents with dopaminergic activity, has been completed. There was a low incidence of side effects among treated subjects, and there was a decrease in self-reported cocaine use and craving. Data collected to date suggest that this combination is safe and possibly effective for treatment of cocaine dependence.